Possible Similar Role of Cytochrome P450 in Primordial Evolution of Species and in Chemical Carcinogenesis

POSSIBLE SIMILAR ROLE OF CYTOCHROME P450 IN PRIMORDIAL EVOLUTION OF SPECIES AND IN CHEMICAL CARCINOGENESIS* ROHAN H. WICKRAMASINGHE and CLAUDE A. VlLLEEi In the current search to understand and treat cancer in man (and other animals) several avenues are being explored. One factor hindering rapid progress in these fields appears to be the variety of agents capable of acting as oncogens under certain situations. The effect of an agent in initiating carcinogenesis may involve its ability to alter the genetic [1,2] machinery of the normal differentiated cell, thereby giving it the capacity to dedifferentiate and become neoplastic and often anaplastic [3] (or to lose its previously specialized function). Such a dedifferentiated cell may then replicate in an unregulated manner, since it is less subject to specialized control mechanisms modifying the growth and behaviour of the other cells in the tissue in which it arose. The tumor often continues growing until the death of the "host." The dedifferentiated nature of cells of neoplastic and anaplastic tissues has sometimes led to comparisons of these with primordial organisms. We discuss here the possibility that one of the mechanisms initiating carcinogenesis may have been effective in causing mutational changes which sometimes led to the establishment of new species following the operation of selectionary factors . We have recently presented [4] considerations which led us to believe that cytochrome P450 probably arose very early in chemical evolution. This heme protein is today widely distributed in the microbial, animal, and plant kingdoms [4, 5]. A principal function of the contemporary enzyme is to incorporate molecular oxygen into a variety of substances [5]. The molecular mechanism by which oxygen is incorporated is not well defined as yet, but it appears that highly reactive intermediates in the hydroxylation reaction may be formed. It is now widely considered *Part of a communication to the College Park Colloquium on "Chemical Evolution ofthe Early Precambrian" at the University of Maryland, October 1975. This work was supported by grant no. 3 ROI CA 16,854-01Sl from the National Cancer Institute, National Institutes of Health, USPHS. tLaboratory of Human Reproduction and Reproductive Biology, Department of Biological Chemistry, Harvard Medical School, 45 Shattuck Street, Boston, Massachusetts 02 11 5. Perspectives in Biology and Medicine · Summer 1976 I 473 that such chemically reactive, electrophilic species may arise from the activation, by cytochrome P450-dependent hydroxylase systems, of chemical carcinogens which are not themselves chemically reactive. These active forms may often be the immediate initiators of carcinogenesis in animals [6, 7]. Examples of this type of carcinogen are the polycyclic hydrocarbons. These (for example, benzo[a]pyrene) do not bind with DNA in the test tube. However, covalent binding to DNA can be demonstrated if the hydrocarbon is activated by incubation with cytochrome P450 contained in liver microsomes in the presence of oxygen and a cofactor which can supply reducing equivalents. It is considered that the reactive intermediates are probably the arene oxides or K-region epoxides of the common carcinogenic hydrocarbons such as phenanthrene, benz[a]anthracene, pyrene, and benzo[a]pyrene [6]. It has been suggested that the presence ofcytochrome P450 in the nuclear membranes of cells may be relevant to the covalent binding to DNA of activated forms of chemical carcinogens [8]. Such activated forms, like other carcinogenic stimuli [9], are also mutagenic to animal cells [6]. A novel technique has been developed by Ames et al. [10, 11] to screen possible carcinogenic agents by their ability to cause mutations in microorganisms . We wish to propose here that the activity of cytochrome P450 of primitive organisms may have played an important role in the mutation of these forms and in species formation. Polynucleotides and some form of genetic apparatus are thought likely to have been components of very early ancestors of contemporary organisms [12, 13]. Different mechanisms may have played roles in causing mutations of early life forms [14], although genetic damage due to external factors such as radiation entering the earth's atmosphere would have been greatly diminished following the evolution of free oxygen and development of the ozone shield. However, chemicals, including those produced endogenously , may have continued to play a part in genetic mutation [15]. While the vast majority...